Respiratory mucosal vaccination of platycodin-functionalized biomimetic nanovaccines for amplifying immune response

Stimulating respiratory immunity helps protect from infection, mitigate disease severity, and curtail transmission. Nonetheless, the majority of current nanovaccines are unable to elicit strong mucosal and systemic immunity owing to suboptimal formulations. Inspired by natural pathogens, we developed virus-like biomimetic nanovaccines in which the heparan sulfate-modified liposome layer (SH-Lip) mimics the "capsid", while platycodin with varying glycosyl side chain structures (PD, PD3, PE) functions as the exposed "spike proteins" to boost immune response and antigen delivery. PD-SH-Lip with the shortest side chain demonstrated an exceptional ability to overcome inherent immune barriers. Contrarily, PD3- and PE-based biomimetic nanovaccines with longer side chain showed superior performance compared with SH-Lip in DC uptake and activation assays, facilitated by Glut-1 transporters, as validated by molecular simulations and mechanism studies. However, in vivo imaging revealed prolonged lung retention and rapid trafficking to the lymph nodes for PD3-SH-Lip with medium chain length. Gene sequencing and Western blot analysis further elucidated synergistical activation of NF-κB/MAPK/NOD-like/TNF signaling pathways. Notably, PD3-SH-Lip induced elevated levels of specific serum IgG and isotype titers, triggering robust CD4⁺ and CD8⁺ T cell immune responses following intrapulmonary administering. Importantly, it exhibited significant CD8⁺ T immune memory function, highlighting its potential to amplify mucosal, cellular, and humoral immunity. By mimicking the structure and infection mechanism of respiratory viruses, this platycodin PD3-functionalized biomimetic nanovaccine presents a promising platform for inhaled immunotherapy.